tbuckley/cabot-search huggingface dataset:
Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis
Authors: Ahmed Ghallab, Daniela González, Ellen Strängberg, Ute Hofmann, Maiju Myllys, Reham Hassan, Zaynab Hobloss, Lisa Brackhagen, Brigitte Begher-Tibbe, Julia C. Duda, Carolin Drenda, Franziska Kappenberg, Joerg Reinders, Adrian Friebel, Mihael Vucur, Monika Turajski, Abdel-latief Seddek, Tahany Abbas, Noha Abdelmageed, Samy A.F. Morad, Walaa Morad, Amira Hamdy, Wiebke Albrecht, Naim Kittana, Mohyeddin Assali, Nachiket Vartak, Christoph van Thriel, Ansam Sous, Patrick Nell, Maria Villar-Fernandez, Cristina Cadenas, Erhan Genc, Rosemarie Marchan, Tom Luedde, Peter Åkerblad, Jan Mattsson, Hanns-Ulrich Marschall, Stefan Hoehme, Guido Stirnimann, Matthias Schwab, Peter Boor, Kerstin Amann, Jessica Schmitz, Jan H. Bräsen, Jörg Rahnenführer, Karolina Edlund, Saul J. Karpen, Benedikt Simbrunner, Thomas Reiberger, Mattias Mandorfer, Michael Trauner, Paul A. Dawson, Erik Lindström, Jan G. Hengstler
Journal: Journal of Hepatology (2023)

Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies.
Guideline‐directed medical therapy in severe heart failure with reduced ejection fraction: An analysis from the HELP‐HF registry
Authors: Daniela Tomasoni, Matteo Pagnesi, Giada Colombo, Mauro Chiarito, Davide Stolfo, Luca Baldetti, Carlo Mario Lombardi, Marianna Adamo, Giuseppe Maggi, Riccardo Maria Inciardi, Ferdinando Loiacono, Marta Maccallini, Alessandro Villaschi, Gaia Gasparini, Marco Montella, Stefano Contessi, Daniele Cocianni, Maria Perotto, Giuseppe Barone, Marco Merlo, Alberto Maria Cappelletti, Giuseppe Rosano, Gianfranco Sinagra, Daniela Pini, Gianluigi Savarese, Marco Metra
Journal: European Journal of Heart Failure (2023)

Persistent symptoms despite guideline-directed medical therapy (GDMT) and poor tolerance of GDMT are hallmarks of patients with advanced heart failure (HF) with reduced ejection fraction (HFrEF). However, real-world data on GDMT use, dose, and prognostic implications are lacking.
EDGE-Gastric Arm A1: Phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer.
Authors: Yelena Y. Janjigian, Do-Youn Oh, Meredith Pelster, Zev A. Wainberg, Edward Allan R. Sison, Jennifer R. Scott, Jack Ronayne, Dana Wishengrad, Joon Rhee, Dimitry S. A. Nuyten, Sun Young Rha
Journal: Journal of Clinical Oncology (2023)

433248 Background: The addition of programmed cell death protein 1 (PD-1) inhibitors to chemotherapy (chemo) confers a survival advantage in 1L gastroesophageal cancers. However, long term outcomes remain poor. Dual PD-1 and anti-T-cell immunoglobulin and ITM domain (TIGIT) blockade increases tumor antigen-specific CD8+ T cell expansion, resulting in potent antitumor activity. The ongoing, multi-arm, global EDGE-Gastric trial (NCT05329766) is evaluating the safety and efficacy of various combinations of the anti-TIGIT Fc-silent monoclonal antibody (mAb) domvanalimab (D) and the anti-PD-1 mAb zimberelimab (Z) in patients (pts) with locally advanced unresectable or metastatic gastric (G)/gastroesophageal junction (GEJ)/esophageal (E) adenocarcinoma. Arm A1 is fully enrolled and results from this 1L arm are presented here. Methods: Patients with previously untreated G/GEJ/E adenocarcinoma received D 1600 mg intravenously (IV) every 4 weeks (Q4W) + Z 480 mg IV Q4W + FOLFOX (oxaliplatin 85 mg/m 2 IV, leucovorin 400 mg/m 2 IV, fluorouracil 400 mg/m 2 IV bolus + 2400 mg/m 2 continuous 46-48-hour IV infusion) Q2W. Primary endpoints are safety and objective response rate (ORR) per RECIST 1.1. Secondary endpoints include ORR by PD-L1 expression and PFS. Results: As of the data cutoff (5 June 2023), 41 pts were enrolled and had the opportunity to have ≥2 imaging assessments. There was an even distribution of pts accrued in Asia vs. rest of world and 63% of pts had gastric cancer. Median time on treatment was 23 weeks (1 to 40), 31 pts (76%) continue on protocol therapy, and there were no deaths on study. Intent-to-treat ORR was 59% (95% CI 42 to 74). Clinical outcomes by PD-L1 status are in the Table. The most common treatment-emergent adverse events (TEAE) were neutropenia (56% of pts), nausea (54%), and anemia (27%). Infusion related reactions were observed in 10% and none were deemed related to D/Z. Grade ≥3 TEAEs occurred in 66% pts, with 54% and 12% having grade ≥3 TEAEs related to FOLFOX and D/Z, respectively. Serious TEAEs occurred in 24% pts: 7% had serious TEAEs related to FOLFOX and no pts had serious TEAEs related to D/Z. TEAE related FOLFOX discontinuation occurred in 13 pts (32%), and in 1 pt due to D/Z. Conclusions: Addition of DZ to FOLFOX showed encouraging ORR and early PFS, particularly in pts with PD-L1-high tumors. The regimen is well tolerated, with a similar AE profile to anti-PD-1+FOLFOX. Updated safety and efficacy will be presented. The randomized phase 3 1L STAR-221 trial of DZ+chemo vs. SOC is underway. Clinical trial information: NCT05329766 . [Table: see text]
Disruption of <i>SUV39H1</i>-Mediated H3K9 Methylation Sustains CAR T-cell Function
Authors: Nayan Jain, Zeguo Zhao, Richard P. Koche, Chenling Antelope, Yosi Gozlan, Antonino Montalbano, David Brocks, Michael Lopez, Anton Dobrin, Yuzhe Shi, Gertrude Gunset, Theodoros Giavridis, Michel Sadelain
Journal: Cancer Discovery (2023)

Suboptimal functional persistence limits the efficacy of adoptive T-cell therapies. CD28-based chimeric antigen receptors (CAR) impart potent effector function to T cells but with a limited lifespan. We show here that the genetic disruption of SUV39H1, which encodes a histone-3, lysine-9 methyl-transferase, enhances the early expansion, long-term persistence, and overall antitumor efficacy of human CAR T cells in leukemia and prostate cancer models. Persisting SUV39H1-edited CAR T cells demonstrate improved expansion and tumor rejection upon multiple rechallenges. Transcriptional and genome accessibility profiling of repeatedly challenged CAR T cells shows improved expression and accessibility of memory transcription factors in SUV39H1-edited CAR T cells. SUV39H1 editing also reduces expression of inhibitory receptors and limits exhaustion in CAR T cells that have undergone multiple rechallenges. Our findings thus demonstrate the potential of epigenetic programming of CAR T cells to balance their function and persistence for improved adoptive cell therapies. T cells engineered with CD28-based CARs possess robust effector function and antigen sensitivity but are hampered by limited persistence, which may result in tumor relapse. We report an epigenetic strategy involving disruption of the SUV39H1-mediated histone-silencing program that promotes the functional persistence of CD28-based CAR T cells. See related article by López-Cobo et al., p. 120. This article is featured in Selected Articles from This Issue, p. 5.
A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer.
Authors: Rui-Hua Xu, Dan-Yun Ruan, Dong-Sheng Zhang, Fu-Rong Liu, Su-Xia Luo, Zhi-Xiang Zhuang, Zhen-Ning Wang, Fu-Nan Liu, Yan-Qiao Zhang, Jian-Wei Yang, Zhen-Dong Chen, Yong-Sheng Wang, Jun-Ye Wang, Xiao-Hua Liang, Xiao-Jie Wu, Yu-Long Zheng, Jian Liu, Xi Shi, Wei Liu, Bo Chen
Journal: Journal of Clinical Oncology (2023)

434420 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced gastric/gastroesophageal junction (G/GEJ) cancer. CMG901, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E (MMAE), has demonstrated potent anti-tumor activity in preclinical studies. Methods: This phase 1 trial included a dose-escalation phase (part A; 0.3-3.4 mg/kg) and a dose-expansion phase (part B; 2.2, 2.6, and 3.0 mg/kg) to evaluate safety, tolerability, and anti-tumor activity of CMG901 in patients (pts) with advanced G/GEJ cancer and other solid tumors. CLDN18.2 expression was not required for study entry in part A, but CLDN18.2 expression of ≥2+ membrane staining intensity in ≥5% tumor cells was required for G/GEJ cancer in part B. CMG901 was administrated intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety/tolerability and maximum tolerated dose (MTD) for part A, and objective response rate (ORR, per RECIST v1.1) and recommended phase 2 dose in part B. Here we present the G/GEJ cancer data from this ongoing trial. Results: MTD was not reached during dose escalation. As of July 24, 2023, 113 G/GEJ cancer pts received CMG901 at doses of 2.2-3.0 mg/kg (6 pts from part A and 107 pts from part B). The median prior lines of systemic therapy were 2 (range 1-6). Most common TEAEs were anaemia (62.8%), vomiting (57.5%), and hypoalbuminaemia (57.5%). Neutrophil count decreased (18.6%) and anaemia (13.3%) were the most frequent grade ≥3 TEAEs. Of 89 evaluable (≥1 post-treatment scan) CLDN18.2-positive pts, confirmed ORR was 32.6% (Table). For all 93 CLDN18.2-positive pts, the median progression-free survival was 4.76 months (95%CI 3.35-6.14) after a median follow-up of 5.98 months. The median overall survival (OS) was not reached, with an OS rate of 56.4% at 9 months. Conclusions: CMG901 demonstrated promising clinical efficacy in CLDN18.2-positive G/GEJ cancer pts, with a manageable safety profile. These results support further evaluation of CMG901 in CLDN18.2-positive G/GEJ cancer. Clinical trial information: NCT04805307 .[Table: see text]
Publisher Correction: Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR–RUNX1
Authors: Li Zhou, Dongxiao Wu, Yabo Zhou, Dianheng Wang, Haixia Fu, Qiusha Huang, Guohui Qin, Jie Chen, Jiadi Lv, Shaoyang Lai, Huafeng Zhang, Ke Tang, Jingwei Ma, Roland Fiskesund, Yi Zhang, Xiaohui Zhang, Bo Huang
Journal: Nature Immunology (2023)
Screening and Preventive Interventions for Oral Health in Adults
Authors: Michael J. Barry, Wanda K. Nicholson, Michael Silverstein, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, Carlos Roberto Jaén, Li Li, Gbenga Ogedegbe, Lori Pbert, Goutham Rao, John M. Ruiz, James Stevermer, Joel Tsevat, Sandra Millon Underwood, John B. Wong
Journal: JAMA (2023)

Importance Oral health is fundamental to health and well-being across the life span. Dental caries (cavities) and periodontal disease (gum disease) are common and often untreated oral health conditions that affect eating, speaking, learning, smiling, and employment potential. Untreated oral health conditions can lead to tooth loss, irreversible tooth damage, and other serious adverse health outcomes. Objective The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate screening and preventive interventions for oral health conditions in adults. Population Asymptomatic adults 18 years or older. Evidence Assessment The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for oral health conditions (eg, dental caries or periodontal disease) performed by primary care clinicians in asymptomatic adults. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of preventive interventions for oral health conditions (eg, dental caries or periodontal disease) performed by primary care clinicians in asymptomatic adults. Recommendations The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine screening performed by primary care clinicians for oral health conditions, including dental caries or periodontal-related disease, in adults. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of preventive interventions performed by primary care clinicians for oral health conditions, including dental caries or periodontal-related disease, in adults. (I statement)
Characterizing the pre-clinical phase of inflammatory bowel disease
Authors: Marie Vibeke Vestergaard, Kristine H. Allin, Gry J. Poulsen, James C. Lee, Tine Jess
Journal: Cell Reports Medicine (2023)

Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnostic phase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset—obtained from the Danish registers—we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD.
CRISPR Screening Identifies Mechanisms of Resistance to KRASG12C and SHP2 Inhibitor Combinations in Non–Small Cell Lung Cancer
Authors: Anirudh Prahallad, Andreas Weiss, Hans Voshol, Grainne Kerr, Kathleen Sprouffske, Tina Yuan, David Ruddy, Morgane Meistertzheim, Malika Kazic-Legueux, Tina Kottarathil, Michelle Piquet, Yichen Cao, Laetitia Martinuzzi-Duboc, Alexandra Buhles, Flavia Adler, Salvatore Mannino, Luca Tordella, Laurent Sansregret, Sauveur-Michel Maira, Diana Graus Porta, Carmine Fedele, Saskia M. Brachmann
Journal: Cancer Research (2023)

Abstract Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non–small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the cyclin-dependent kinase 4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple, or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 coinhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments. Significance: Identification of resistance mechanisms to KRASG12C/SHP2 coinhibition highlights the need for additional combination therapies for lung cancer beyond on-pathway combinations and offers the basis for development of more effective combination approaches. See related commentary by Johnson and Haigis, p. 4005
<i>ARL6IP1</i> gene delivery reduces neuroinflammation and neurodegenerative pathology in hereditary spastic paraplegia model
Authors: Jung Hwa Lim, Hyun Mi Kang, Dae Hun Kim, Bohyeon Jeong, Da Yong Lee, Jae-Ran Lee, Jeong Yeob Baek, Hyun-Soo Cho, Mi-Young Son, Dae Soo Kim, Nam-Soon Kim, Cho-Rok Jung
Journal: The Journal of Experimental Medicine (2023)

ARL6IP1 is implicated in hereditary spastic paraplegia (HSP), but the specific pathogenic mechanism leading to neurodegeneration has not been elucidated. Here, we clarified the molecular mechanism of ARL6IP1 in HSP using in vitro and in vivo models. The Arl6ip1 knockout (KO) mouse model was generated to represent the clinically involved frameshift mutations and mimicked the HSP phenotypes. Notably, in vivo brain histopathological analysis revealed demyelination of the axon and neuroinflammation in the white matter, including the corticospinal tract. In in vitro experiments, ARL6IP1 silencing caused cell death during neuronal differentiation and mitochondrial dysfunction by dysregulated autophagy. ARL6IP1 localized on mitochondria-associated membranes (MAMs) to maintain endoplasmic reticulum and mitochondrial homeostasis via direct interaction with LC3B and BCl2L13. ARL6IP1 played a crucial role in connecting the endoplasmic reticulum and mitochondria as a member of MAMs. ARL6IP1 gene therapy reduced HSP phenotypes and restored pathophysiological changes in the Arl6ip1 KO model. Our results established that ARL6IP1 could be a potential target for HSP gene therapy.
TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Authors: A. Cole Edwards, Clint A. Stalnecker, Alexis Jean Morales, Khalilah E. Taylor, Jennifer E. Klomp, Jeffrey A. Klomp, Andrew M. Waters, Niranjan Sudhakar, Jill Hallin, Tracy T. Tang, Peter Olson, Leonard Post, James G. Christensen, Adrienne D. Cox, Channing J. Der
Journal: Cancer Research (2023)

Abstract Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRASG12C mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the antiproliferative and proapoptotic effects of KRASG12C inhibitor (G12Ci) treatment in KRASG12C-mutant cancer cell lines. Conversely, genetic suppression of YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor–dependent mechanisms, which phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1, and MYC) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K–AKT–mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor antitumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the antitumor efficacy of KRAS-targeted therapies. Significance: YAP1/TAZ-TEAD activation compensates for loss of KRAS effector signaling, establishing a mechanistic basis for concurrent inhibition of TEAD to enhance the efficacy of KRASG12C-selective inhibitor treatment of KRASG12C-mutant cancers. See related commentary by Johnson and Haigis, p. 4005
Author Correction: Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans
Authors: Shuhei Murase, Naoyoshi Sakitani, Takahiro Maekawa, Daisuke Yoshino, Kouji Takano, Ayumu Konno, Hirokazu Hirai, Taku Saito, Sakae Tanaka, Keisuke Shinohara, Takuya Kishi, Yuki Yoshikawa, Takamasa Sakai, Makoto Ayaori, Hirohiko Inanami, Koji Tomiyasu, Atsushi Takashima, Toru Ogata, Hirotsugu Tsuchimochi, Shinya Sato, Shigeyoshi Saito, Kohzoh Yoshino, Yuiko Matsuura, Kenichi Funamoto, Hiroki Ochi, Masahiro Shinohara, Motoshi Nagao, Yasuhiro Sawada
Journal: Nature Biomedical Engineering (2023)
Navigating access to medical gender affirmation in Tasmania, Australia: an exploratory study
Authors: Ruby Grant, Ash Russell, Sharon Dane, Isabel Dunn
Journal: International Journal of Transgender Health (2023)

Gender affirmation through hormone replacement therapies and surgery can significantly improve the health and wellbeing of some transgender, nonbinary, and gender diverse people. Despite the well-documented benefits of gender affirming care, barriers persist for many trans and gender diverse people, particularly those in rural areas.
Error in Byline
Journal: JAMA Network Open (2023)

Rohit Vashisht, PhD; Ayan Patel, MS; Lisa Dahm, PhD; Cora Han, JD; Kathryn E. Medders, PharmD, PhD; Robert Mowers, PharmD; Carrie L. Byington, MD; Suneil K. Koliwad, MD, PhD; Atul J. Butte, MD, PhD
Loss of ADAR1 in macrophages in combination with interferon gamma suppresses tumor growth by remodeling the tumor microenvironment
Authors: Weiwei Lin, Yikai Luo, Jie Wu, Haowan Zhang, Ge Jin, Chahua Guo, Hang Zhou, Han Liang, Xiaoyan Xu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown. Methods We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain the mechanistic insights, we performed human cytokine arrays to identify differentially secreted cytokines in response to ADAR1 perturbations in THP-1 cells. Furthermore, we examined the effects of ADAR1 loss and IFN-γ treatment on vessel formation through immunohistochemical staining of mouse tumor sections and tube-forming experiments using HUVEC and SVEC4-10 cells. We also assessed the effects on CD8 + T cells using immunofluorescent and immunohistochemical staining and flow cytometry. To explore the translational potential, we examined the consequences of injecting ADAR1-deficient macrophages alongside IFN-γ treatment on tumor growth in LLC-tumor-bearing mice. Results Our analysis on public data suggests that ADAR1 loss in macrophages promotes antitumor immunity as in cancer cells. Indeed, ADAR1 loss in macrophages combined with IFN-γ treatment results in tumor regression in diverse disease mouse models. Mechanistically, the loss of ADAR1 in macrophages leads to the differential secretion of key cytokines: it inhibits the translation of CCL20, GDF15, IL-18BP, and TIM-3 by activating PKR/EIF2α signaling but increases the secretion of IFN-γ through transcriptional upregulation and interleukin (IL)-18 due to the 5'UTR uORF. Consequently, decreased CCL20 and GDF15 and increased IFN-γ suppress angiogenesis, while decreased IL-18BP and TIM-3 and increased IL-18 induce antitumor immunity by enhancing cytotoxicity of CD8 + T cells. We further demonstrate that combination therapy of injecting ADAR1-deficient macrophages and IFN-γ effectively suppresses tumors in vivo. Conclusion This study provides a comprehensive elucidation of how ADAR1 loss within macrophages contributes to the establishment of an antitumor microenvironment, suggesting the therapeutic potential of targeting ADAR1 beyond the scope of cancer cells.